Effects of rolipram and cilostamide on renal functions and cAMP release in anesthetized dogs

Tanahashi, Masayuki; Hara, Sunao; Saitoh, Kohji; Hisa, Hiroaki; Satoh, Susumu

doi:10.1016/s0021-5198(19)34166-6

Cited by 4 publications

(2 citation statements)

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“…In animal studies, PDE inhibitors stimulated lipolysis and free fatty acid synthesis, and improved insulin resistance and endothelial dysfunction [ 14 , 31 , 32 ]. It also affects peripheral and renal blood flow [ 33 , 34 ], suggesting the possibility of attenuating renal tubular blood flow. In the present study, PTX did not influence HIF-1α expression in NRK cells stimulated with CoCl 2 and HG.…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase Inhibitor Improves Renal Tubulointerstitial Hypoxia of the Diabetic Rat Kidney

Sun

Lee

Han

et al. 2012

Korean J Intern Med

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Background/AimsRenal hypoxia is involved in the pathogenesis of diabetic nephropathy. Pentoxifyllin (PTX), a nonselective phosphodiesterase inhibitor, is used to attenuate peripheral vascular diseases. To determine whether PTX can improve renal hypoxia, we investigated its effect in the streptozocin (STZ)-induced diabetic kidney.MethodsPTX (40 mg/kg, PO) was administered to STZ-induced diabetic rats for 8 weeks. To determine tissue hypoxia, we examined hypoxic inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1) levels. We also tested the effect of PTX on HIF-1α in renal tubule cells.ResultsPTX reduced the increased protein creatinine ratio in diabetic rats at 8 weeks. HIF-1α, VEGF, and GLUT-1 mRNA expression increased significantly, and the expression of HO-1 also tended to increase in diabetic rats. PTX significantly decreased mRNA expression of HIF-1α and VEGF at 4 and 8 weeks, and decreased HO-1 and GLUT-1 at 4 weeks. The expression of HIF-1α protein was significantly increased at 4 and 8 weeks in tubules in the diabetic rat kidney. PTX tended to decrease HIF-1α protein expression at 8 weeks. To examine whether PTX had a direct effect on renal tubules, normal rat kidney cells were stimulated with CoCl2 (100 µM), which enhanced HIF-1α mRNA and protein levels under low glucose conditions (5.5 mM). Their expressions were similar even after high glucose (30 mM) treatment. PTX had no effect on HIF-1α expression.ConclusionsPTX attenuates tubular hypoxia in the diabetic kidney.

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Section: Discussionmentioning

confidence: 99%

Phosphodiesterase Inhibitor Improves Renal Tubulointerstitial Hypoxia of the Diabetic Rat Kidney

Sun

Lee

Han

et al. 2012

Korean J Intern Med

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“…For example, in the volume-resuscitated septic infant with acute cardiac dysfunction, PDE3 inhibitors increase levels of both cAMP and cGMP to improve cardiac contractility ( Barton et al, 1996 ; Irazuzta et al, 2007 ; Meyer et al, 2011 ) and increase survival ( de Oliveira et al, 2008 ; Brierley et al, 2009 ). PDE4 is selective for cAMP ( Boswell-Smith et al, 2006 ; Maurice et al, 2014 ) and in adult animal model of sepsis, inhibitors of PDE4 reduce systemic vascular resistance ( Carcillo et al, 1996 ), improve cardiac contractility ( Thomas et al, 2003 ) and improve renal function ( Carcillo et al, 1996 ; Tanahashi et al, 1999 ; Holthoff et al, 2013 ). PDE4 inhibitors also have potent anti-inflammatory activity and reduce microvascular leakage ( Sanz et al, 2007 ; Schick et al, 2012 ), all of which could have added benefits in infants with severe sepsis.…”

Section: Introductionmentioning

confidence: 99%

Rolipram Improves Outcome in a Rat Model of Infant Sepsis-Induced Cardiorenal Syndrome

Sims

Singh

et al. 2017

Front. Pharmacol.

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While the mortality rate associated with sepsis in children has fallen over the years, it still remains unacceptably high. The development of both acute cardiac dysfunction and acute kidney injury during severe sepsis is categorized as type 5 cardiorenal syndrome (CRS) and is poorly understood in infants. To address this lack of understanding and the need for an appropriate animal model in which to conduct relevant preclinical studies, we developed a model of infant sepsis-induced CRS in rat pups then evaluated the therapeutic potential of the phosphodiesterase (PDE) 4 inhibitor, rolipram. Rat pups at 17–18-days old were subjected to cecal ligation and puncture (CLP) to induce fecal polymicrobial sepsis. Uptake of Evans Blue dye was used to assess renal microvascular leakage. Intravital videomicroscopy was used to assess renal microvascular perfusion and oxidant generation. Glomerular filtration rate (GFR) was used to assess renal function. Left ventricular (LV) catheterization and echocardiography were used to assess cardiac function. Impairment of both cardiac and renal function developed rapidly following CLP, indicating type 5 CRS. Most notable were the rapid decline in LV diastolic function, the decline in cardiac output, renal microvascular failure, and the decline in GFR. A dose-response study with rolipram determined 0.1 mg/kg, ip as the lowest most efficacious dose to protect the renal microcirculation. Rolipram was then evaluated using a clinically relevant delayed dosing paradigm (a single dose at 6 h post-CLP). With delayed dosing, rolipram restored the renal microcirculation and reduced microvascular leakage but did not reduce oxidant generation in the kidney nor restore GFR. In contrast, delayed dosing with rolipram restored cardiac function. Rolipram also improved 4-days survival. In summary, CLP in the rat pup produces a clinically relevant pediatric model of sepsis-induced CRS. The PDE4 inhibitor rolipram was effective in improving renal microvascular function and cardiac function, which improved mortality. These findings suggest that rolipram should be evaluated further as adjunctive therapy for the septic infant with CRS.

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Effects of NKH477 on renal functions and cyclic AMP production in anesthetized dogs

Tanahashi

Hara

Yoshida

et al. 1999

European Journal of Pharmacology

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Effects of rolipram and cilostamide on renal functions and cAMP release in anesthetized dogs

Cited by 4 publications

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Phosphodiesterase Inhibitor Improves Renal Tubulointerstitial Hypoxia of the Diabetic Rat Kidney

Phosphodiesterase Inhibitor Improves Renal Tubulointerstitial Hypoxia of the Diabetic Rat Kidney

Rolipram Improves Outcome in a Rat Model of Infant Sepsis-Induced Cardiorenal Syndrome

Effects of NKH477 on renal functions and cyclic AMP production in anesthetized dogs

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